ACCORD BP

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ACCORD Study Group. "Effects of intensive blood-pressure control in type 2 diabetes mellitus". The New England Journal of Medicine. 2010. 362(17):1575-1585.
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Clinical Question

In patients with T2DM at high risk for CV events, does intensive BP control (SBP <120 mmHg) reduce rates of nonfatal MI, nonfatal stroke, or CV mortality when compared to standard BP control (SBP <140 mmHg)?

Bottom Line

In patients with T2DM at high risk for CV events, targeting SBP <120 mmHg did not reduce rates of nonfatal MI, nonfatal stroke, or CV mortality when compared to a target SBP <140 mmHg.

Major Points

Patients with T2DM are at elevated risk for CVD. HTN is an independent risk factor for CVD. The JNC 7 recommended targeting SBP to 130 mmHg despite a lack of large RCTs supporting this recommendation.

The 2010 Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD BP) trial randomized 4,733 patients with T2DM at elevated risk for CVD to intensive BP control (SBP <120 mmHg) or standard BP control (SBP <140 mmHg) in an open-label fashion. With a median follow-up of 4.7 years, there was no difference in nonfatal MI, nonfatal stroke, or CV mortality between the two groups. There was a very small reduction in stroke risk with intensive BP control (0.32%/yr vs. 0.53%/yr), though NNT was 476 patients per year. The intensive therapy group was on more medications and had a higher rate of serious adverse events due to medications (3.3% vs. 1.27%; NNH 49). Of note, the intensive group's SBP was close to the goal of <120 mmHg, the standard therapy group's average SBP was in the low-130s.

Given the findings of ACCORD BP, the JNC 8 has raised its goal blood pressure targets for diabetics to <140/90.

Guidelines

JNC 8 hypertension guidelines (2014, adapted)[1]

  • General population, age <60 years - Start pharmacologic therapy if:
    • SBP ≥140 mmHg for goal SBP <140 mmHg (expert opinion, grade E)
    • DBP ≥90 mmHg for goal DBP <90 mmHg (strong recommendation, grade A for ages 30-59; expert opinion, grade E for ages 18-29 years)
  • General population, age ≥60 years - Start pharmacologic therapy if:
    • SBP ≥150 mmHg for goal SBP <150 mmHg (strong recommendation, grade A)
      • Continue any well-tolerated SBP treatments for goal SBP <140 mmHg without modifications (expert opinion, grade E)
    • DBP ≥90 mmHg for goal DBP <90 mmHg (strong recommendation, grade A)
  • CKD, age ≥18 years
    • Start pharmacologic therapy if SBP or DBP is ≥140 or 90 mmHg, respectively for goal <140/90 (expert opinion, grade E)
    • Regardless of race of diabetic status, initial or add-on therapy as ACE-inhibitor or ARB to improve outcomes of kidney disease (moderate recommendation, grade B)
  • DM, age ≥18 years - Start pharmacologic therapy if SBP or DBP is ≥140 or 90 mmHg, respectively for goal <140/90 (expert opinion, grade E)
  • General non-black population including DM - Initial therapy with a thiazide, CCB, ACE-inhibitor, or ARB (moderate recommendation, grade B)
  • General black population including DM - Intial therapy with a thiazide or CCB (moderate recommendation, grade B for general black population; weak recommendation, grade C for black population with DM)
  • Treatment goals (expert opinion, grade E)
    • If refractory BP at the end of one month, increase dose of monotherapy or add second agent (thiazide, CCB, ACE-inhibitor, or ARB)
    • If refractory BP on two medications, add third agent (thiazide, CCB, ACE-inhibitor, or ARB)
    • If goal not reached with three drugs then other classes can be used
    • Do not use ACE-inhibitors and ARBs together
    • Consider referral to hypertension specialist if refractory hypertension

ADA DM (2013, adapted)[2]

  • Treat HTN to a SBP <140 mmHg (grade B) and DBP <80 (grade B)
    • Goal SBP <130 may be appropriate for some (eg, younger individuals) if it can be achieved without burdensome treatment (grade C)
  • BP-reducing lifestyle interventions when BP >120/80 (grade B), these include DASH-style diet with reduced sodium and increased potassium, moderate alcohol, and increased physical activity (grade B)
  • BP-control with ACE-inhibitor or ARB, can substitute one class for the other if poorly tolerated (grade C)
  • Administer ≥1 antihypertensive at bedtime (grade A)

Design

  • Multicenter, randomized, controlled, open-label trial
  • Setting: 77 centers in Canada and United States
  • N=4,733 (goal sample size 4,200)
    • Intensive BP control (n=2,362)
    • Conventional BP control (n=2,371)
  • Enrollment: 2001 and 2003-2005
  • Mean follow-up: 4.7 years
  • Primary Outcome: Nonfatal MI, nonfatal stroke, or CV mortality

Population

Inclusion Criteria

  • Type 2 diabetes mellitus
  • Hemoglobin A1C ≥7.5%
  • Age ≥40 years with CVD
  • Age ≥55 years with any of the following:
    • Atherosclerosis
    • Albuminuria
    • LVH
    • ≥2 CV risk factors (dyslipidemia, hypertension, smoking, or obesity)

Exclusion Criteria

  • BMI >45 kg/m2
  • Creatinine >1.5mg/dL (132.6 umol/L)
  • Other serious illness
  • Age ≥80 was added in 2003

Baseline Characteristics

From both groups combined.

  • Demographics: Age 62 years, 48% female
    • Race or ethnic group: Non-Hispanic white 61%, black 24%, Hispanic 7.0%
    • Education: Less than high school 16%, high school or GED 27%, some college 32%, college or higher degree 24%
  • PMH: Prior CV event 34%, prior HF 4%, smoker 13.2% (former smoker 42%),
  • Baseline health data: Weight 92 kg, BMI 21 kg/m2, BP 139/76 mmHg
  • Diabetes data: Duration of diabetes 10 years, hemoglobin A1c 8.3%, fasting glucose 175 mg/dL
  • Other laboratory data: Tchol 192 mg/dL, LDL 110 mg/dL, women's HDL 51 mg/dL, men's HDL 42 mg/dL, trigylcerides 147 mg/dL, potassium 4.5 mg/dL, creatinine 0.9 mg/dL (eGFR 92 mL/min/1.73 m2, urine albumin:creatinine 14.3

Interventions

  • Open-label randomization to a group:
    • Intensive BP control - Goal SBP <120 mmHg
    • Standard BP control - Goal SBP <140 mmHg
  • BP was controlled with conventional therapies

Outcomes

Comparisons are intensive BP control vs. standard BP control.

Primary Outcomes

Nonfatal MI, nonfatal stroke, or CV mortality
1.87%/yr vs. 2.09%/yr (HR 0.88; 95% CI 0.73-1.06; P=0.20)

Secondary Outcomes

Nonfatal myocardial infarction
1.13%/yr vs. 1.28%/yr (HR 0.87; 95% CI 0.68-1.10; P=0.25)
Stroke
Any: 0.32%/yr vs. 0.53%/yr (HR 0.59; 95% CI 0.39-0.89; P=0.01; NNT 476/yr)
Nonfatal: 0.30%/yr vs. 0.47%/yr (HR 0.63; 95% CI 0.41-0.96; P=0.03; NNT 588/yr)
All-cause mortality
1.28%/yr vs. 1.19%/yr (HR 1.07; 95% CI 0.85-1.35; P=0.55)
CV mortality
0.52%/yr vs. 0.49%/yr (HR 1.06; 95% CI 0.74-1.52; P=0.74)
Primary outcome or revascularization or nonfatal heart failure
5.10%/yr vs. 5.31%/yr (HR 0.95; 95% CI 0.84-1.07; P=0.40)
Major coronary disease event
Fatal coronary event, nonfatal MI, or unstable angina.
2.31%/yr vs. 2.41%/yr (HR 0.94; 95% CI 0.79-1.12; P=0.50)
Fatal or nonfatal HF
0.73%/yr vs. 0.78%/yr (HR 0.94; 95% CI 0.70-1.26; P=0.67)

Additional Analyses

BP at month 4
SBP: 119.3 vs. 133.5 mmHg
DBP: 64.4 vs. 70.5 mmHg
BP medications in first year
3.4 vs. 2.1
Hemoglobin A1c
7.6% vs. 7.5% (P=0.13)
Cholesterol
LDL: 98.7 vs. 96.8 mg/dL (P=0.10)
HDL: 46.7 vs. 47.8 mg/dL (P=0.02)
TG: 138 vs. 131 mg/dL (P=0.001)
Renal laboratory
eGFR: 74.8 vs. 80.6 mL/min/1.73 m2 (P<0.001)
Urinary albumin:creatinine: 12.6 vs. 14.9 (ratio is mg:g; P<0.001)
Microalbuminuria: 30.2% vs. 32.3% (P=0.13)
Macroalbuminuria: 6.6% vs. 8.7% (P=0.009; NNT 47)

Subgroup Analysis

No significant interaction among prespecified subgroups, including gender, age, ethnicity, prior CVD, glycemia goal assignment, baseline A1c, baseline BP, and number of anti-HTN medications at baseline.

Adverse Events

Serious
Defined as life-threatening, causing permanent disability, or necessitating hospitalization.
Attributed to BP medications: 3.3% vs. 1.27% (P<0.001; NNH 49)
Hypotension: 0.7% vs. 0.04% (P<0.001; NNH 152)
Syncope: 0.5% vs. 0.21% (P=0.10)
Bradycardia or arrhythmia: 0.5% vs. 0.13% (P=0.02; NNH 270)
Hyperkalemia: 0.4% vs. 0.04% (P=0.01; NNH 278)
Angioedema: 0.3% vs. 0.17% (P=0.55)
Renal Failure: 0.2% vs. 0.04% (P=0.12)
ESRD or need for dialysis 2.5% vs. 2.4% (P=0.93)
Laboratory abnormalities
Potassium <3.2 mmol/L: 2.1% vs. 1.1% (P=0.01; NNH 100)
Potassium >5.9 mmol/L: 3.1% vs. 3.0% (P=0.93)
eGFR <30 mL/min/1.73 m2: 4.2% vs. 2.2% (P<0.001; NNH 50)
Quality of life
Hives or swelling: 8.8% vs. 8.8% (P=1.00)
Dizziness upon standing: 44.3% vs. 40.3% (P=0.36)

Criticisms

  • Patients were late into disease process and may have missed opportunity for benefit (mean age 62, 34% had CV events before trial, avg 10 yrs of DM)
  • Not blinded
  • Underpowered because of the lower-than-expected rate of events[3]
  • Duration of follow-up may not have been sufficient
  • Did not compare the JNC 7's recommendation of 130 mmHg to 140 mmHg
  • Not powered to detect renal outcomes[4]
  • BP lowering may have been too aggressive and caused harm[5]
  • Few individuals of Hispanic ethnicity enrolled

Funding

  • Multiple public sources (CDC and NIH including NHLBI, NIDDK, NIA, National Eye Institute)
  • Various Drug companies donated medications, equipment, and supplies but had no role in the design of the study, the accrual or analysis of the data, or the preparation of the manuscript

Further Reading

  1. James PA, et al. "2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8)." JAMA. 2014;311(5):507-20
  2. No authors listed. "Executive summary: Standards of medical care in diabetes - 2013." Diabetes Care. 2013;36 supplement 1:S4-S10.
  3. Nilsson PM. "Editorial: ACCORD and risk-factor control in type 2 diabetes." The New England Journal of Medicine. 2010;362:1628-1630.
  4. Elley C and Selak V. "ACP Journal Club: Intensive blood pressure control did not prevent major CV events more than standard control in type 2 diabetes." Annals of Internal Medicine. 2010;153(2):JC1-JC4.
  5. Multiple authors. "Correspondence: Blood pressure control in type 2 diabetes. 2010;363:695-697.